Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI.
The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)-dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pretreatment of baboons with a novel anti-human FXI monoclonal antibody (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and beta-thromboglobulin (betaTG) formation measured immediately downstream from thrombi forming within collagen-coated vascular grafts. FXI inhibition with aXIMab limited platelet and fibrin deposition in 4-mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2-mm diameter grafts without affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, supporting the concept that FXI blockade may offer therapeutic advantages over other antithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagen-coated flow chamber, independent of factor XII and factor VII. These data suggest that endogenous FXI contributes to arterial thrombus propagation through a striking amplification of thrombin generation at the thrombus luminal surface.
Tucker
Erik I
EI
Departments of Biomedical Engineering, Oregon Health & Science University School of Medicine, Portland, OR 97239, USA.
Marzec
Ulla M
UM
White
Tara C
TC
Hurst
Sawan
S
Rugonyi
Sandra
S
McCarty
Owen J T
OJ
Gailani
David
D
Gruber
András
A
Hanson
Stephen R
SR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D005172:Factor XI / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D005174:Factor XII / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D008297:Male; D010215:Papio; D015539:Platelet Activation / Q000276:immunology; D013917:Thrombin / Q000378:metabolism*; D013927:Thrombosis / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D005174:Factor XII; D005337:Fibrin; D003094:Collagen; D005172:Factor XI; D013917:Thrombin